10,10-dihydro-10-[(substituted-carbonyl)imino]-10-phenyl-10H-phenoxaphosphines

ABSTRACT

Novel 10,10-Dihydro-10-[(substituted carbonyl)imino]-10-phenyl-10H-phenoxaphines of the formula: ##STR1## wherein A is selected from the group consisting of hydrogen and COOR 1 , where, when A is hydrogen the compound is in the form of a water soluble salt HnX, where n is an integer 1 or 2 and X is selected from the group consisting of sulfate, trefluoroacetate, bromide and chloride and R 1  is selected from the group consisting of straight or branched chain alkyl(C 1  -C 4 ), alkenyl(C 2  -C 4 ), alkynyl(C 2  -C 4 ), cycloalkyl(C 3  -C 6 ), cycloalkyl(C 3  -C 6 )methyl, benzyl, pyridylmethyl and tetrahydro-3-furanyl; methods for using these compounds for effecting diuresis, treating hypertension and edema and lowering plasma renin activity in mammals; pharmaceutical compositions of matter containing these compounds and processes for their preparation.

This is a division of application Ser. No. 836,278, filed Mar. 5, 1986,now U.S. Pat. No. 4,689,324, issue date Aug. 25, 1987.

SUMMARY OF THE INVENTION

This invention is concerned with new compounds of the formula: ##STR2##wherein A is selected from the group consisting of hydrogen and COOR₁,where, when A is hydrogen the compound is in the form of a water solublesalt HnX, where n is an integer 1 or 2 and X is selected from the groupconsisting of sulfate, trifluoroacetate, bromide and chloride and R₁ isselected from the group consisting of straight or branched chainalkyl(C₁ -C₄), alkenyl(C₂ -C₄), alkynyl(C₂ -C₄), cycloalkyl(C₃ -C₆),cycloalkyl(C₃ -C₆)methyl, benzyl, pyridylmethyl andtetrahydro-3-furanyl.

This invention is also concerned with methods of using these compoundsto effect diuresis, treat hypertension and edema, and lower plasma reninactivity in mammals, as well as pharmaceutical compositions of mattercontaining these compounds and processes for the preparation of thesecompounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided methods ofeffecting diuresis and lowering plasma renin activity in a mammal whichcomprises administering to said mammal a therapeutically effectiveamount of a compound selected from those of Formula I.

The compounds of Formula I find utility as diuretics and cardiotonics inmammals and as such may be used as the drug of choice for the treatmentof edema caused by cardiac, hepatic, pulmonary and renal diseases, aswell as drug-induced fluid and salt retention. These compounds may alsobe useful as hypotensive agents upon chronic administration by virtue oftheir diuretic activity. As cardiotonic agents, these compounds maylikewise be useful in the treatment of congestive heart failure.

The action of the currently available diuretics can be depicted by thefollowing diagram: ##STR3##

In contrast, the compounds of the present invention acting on the kidneylower plasma renin activity, thereby effecting non-attenuated sodiumloss and minimal potassium loss, and preventing adrenal compensation.##STR4##

The compounds of this invention may be prepared as described in thefollowing flowcharts and text. ##STR5##

In accordance with Flowchart A, 10-phenyl-10H-phenoxaphosphine (1),which is a known compound [J. Granoth, et al., J. Chem. Soc., Perkin II,pp. 697-700 (1972)], is reacted with a carbonazidate (2), where R₁ isalkyl(C₁ -C₄) or phenylmethyl in ether, giving the products (3). Therequisite N₃ COOR₁ are obtained by treating carbazidic esters of thestructure H₂ NNHCOOR₁ with nitrous acid, or by the action ofchloroformic esters of the structure ClCOOR₁, with lithium or sodiumazide. ##STR6##

In accordance with Flowchart B, lithium azide and trifluoroacetic acidare reacted in acetonitrile at -10° to +10° C. for 1-2 hours, then witha solution of 10-phenyl-10H-phenoxaphosphine (1) andN,N-carbonyldiimidazole in acetonitrile at room temperature for 4-8hours, giving10,10-dihydro-10-[(1H-imidazol-1-ylcarbonyl)-imino]-10-phenyl-10H-phenoxaphosphine(5) which is then reacted with a sodium alkoxide (6a) prepared from analcohol (6) and sodium hydride where R₁ is selected from the groupcomprising alkenyl(C₂ -C₄), alkynyl(C₂ -C₄), cycloalkyl(C₃ -C₆),cycloalkyl(C₃ -C₆)methyl, pyridylmethyl and 3-hydroxytetrahydrofuran in1,2-dimethoxyethane, giving the products (3). ##STR7##

In accordance with Flowchart C, 10-phenyl-10H-phenoxaphosphine (1) isreacted with t-butyl carbonazidate in ether, giving10-[[(1,1-dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphine(7) which is then reacted with an appropriate acid HnX and isolated fromether, giving compounds (8) where n and X are as described above.##STR8##

In accordance with Flowchart D, 10-phenyl-10H-phenoxaphosphine (1) isreacted with hydroxylamine O-sulfonic acid in anhydrous methanol forseveral hours, then added to ether giving10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine sulfate. ##STR9##

In accordance with Flowchart E,10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine sulfate (8) andtriethylamine in acetonitrile are reacted with a chloroformate ClCOOR₁,where R₁ is as described above, for several hours, giving (3).

Inhibition of evoked increase of plasma renin activity was determined bythe following test.

Compounds were tested for their ability to prevent drug-inducedelevation of plasma renin activity (PRA) in concious, male Wistar rats(180-200 g, Charles River Lab.). PRA elevation was induced by a combinedoral provocative treatment (C) of hydrochlorothiazide (10 mg/kg) and1-(3-benzoyl-3-mercapto-2-methylpropionyl-L-proline, acetate (U.S. Pat.No. 4,226,775) (1 mg/kg), prepared by compounding in a mortar and pestlewith preboiled 3% starch suspension. This treatment provided the dailymaximum PRA. The daily minimum PRA was obtained from rats given oralstarch suspension (S) alone. The magnitude of drug effect on PRAelevation was ascertained from rats pretreated orally with test agent(D), at the indicated doses, 30 minutes prior to administration ofprovocative treatment (C). The test agent was also compounded inpreboiled 3% starch suspension. The dose volumes for both pretreatmentand provocative treatment were 2 ml/kg. One hour after provocativetreatment the rats were sacrificed by decapitation and the first 3seconds of blood collected in two chilled vacutainer tubes containing 40μl of 150 mg/ml tripotassium EDTA. The plasmas, which were obtained bycentrifugation for 20 minutes at 4° C. and 3000×G, were incubated (oneof each pair at 37° C., the other at 4° C.) at pH 6.8 in 50 mM phosphatebuffer to produce angiotensin I. The incubates contained peptidaseinhibitors to prevent angiotensin I degradation and the incubationbuffer contained 1 mg/ml lysozyme (Sigma Grade III) used as anantiabsorbant. The incubates were diluted 20 fold in cold 100 mM trisbuffer (pH adjusted to 7.4 with glacial acetic acid) also containing 1mg/ml lysozyme, and then frozen. Diluted incubates were assayed within 3days for angiotensin I content by radioimmunoassay according to amodification of the method of Haber, et al., J. Clin. Endocrin., 29,1349-1355 (1969).

PRA is calculated as follows:

    PRA(mg AI/hour/ml plasma)=PRA 37° C.-PRA 4° C.

Percent inhibition of PRA elevation is calculated as follows: ##EQU1##

The results of this test on a representative compound of this inventionappear in Table I.

                  TABLE I                                                         ______________________________________                                        Percent Inhibition of Plasma Renin Elevation                                                   Dose     Av. % Inhibition                                    Compound         (mg/kg)  (No. of Rats)                                       ______________________________________                                        10-[(Ethoxycarbonyl)imino]-                                                                    1        33(5)                                               10,10-dihydro-10-phenyl-                                                                       2        54(5)                                               10 .sub.--H--phenoxaphosphine                                                                  4        78(5)                                                                8        91(5)                                                                25       84(5)                                               10,10-Dihydro-10-imino-                                                                        1        38(7)                                               10-phenyl-10 .sub.--H--phenoxa-                                                                4         31(13)                                             phosphine, sulfate                                                                             4         42(13)                                                              8         67(10)                                             ______________________________________                                    

The diuretic activity of the compounds of this invention was determinedaccording to the method of Chan, P. S. and Poorvin, D., Sequentialmethod for combined screening antihypertensive and diuretic agents inthe same spontaneously hypertensive rat. Clinical and ExperimentalHypertension, 1 (6), 817-830 (1979).

Male spontaneously hypertensive rats of Okamoto strain, 16 weeks old,Taconic Farms Inc., were used in the test. These rats were kept onPurina laboratory chow and tap water ad libitum for 8 weeks before use.The male adult rats (about 300 g) were dosed by gavage with a testcompound at 100 mg/kg at zero hour with the exception of one male adultrat in which the test compound dosage was 50 mg/kg. The test compoundwas suspended in 3% preboiled starch at 50 mg/ml. Each rat was put inmetabolism cage. The 0-5 hour urine was collected and urinary sodium andpotassium were determined using a Beckman Astra 4. The results of thistest on representative compounds of this invention appear in Table II.

                  TABLE II                                                        ______________________________________                                        Diuretic Activity in Spontaneously Hypertensive Rats                                                  Sodium                                                               Volume   MEQ/5    Potassium                                    Compound       ml       Hours    MEQ/5 Hours                                  ______________________________________                                        10,10-Dihydro-10-[(eth-                                                                      19.0     2.20     0.49                                         oxycarbonyl)imino]-10-                                                        phenyl-10H--phenoxaphos-                                                      phine                                                                         10,10-Dihydro-10-[(meth-                                                                     14.0     1.48     0.74                                         oxycarbonyl)imino]-10-                                                        phenyl-10 .sub.--H--phenoxaphos-                                              phine                                                                         10,10-Dihydro-10-[[(1-                                                                       16.5     2.30     0.66                                         methylethoxy)carbonyl]-                                                       imino]-10-phenyl-                                                             10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-[[(2-                                                                       12.8     1.63     0.64                                         methylpropoxy)carbonyl]-                                                      imino]-10-phenyl-                                                             10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-phenyl-                                                                     12.3     1.32     0.56                                         10-[[(phenylmethoxy)car-                                                      bonyl]imino]-10 .sub.--H--phen-                                               oxaphosphine                                                                  10-[[(Cyclopropylmeth-                                                                       10.8     1.41     0.75                                         oxy)carbonyl]imino]-                                                          10,10-dihydro-10-phenyl-                                                      10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-phenyl-                                                                     14.3     1.49     0.73                                         10-[[[(tetrahydro-3-                                                          furanyl)oxy]carbonyl]-                                                        imino]-10 .sub.--H--phenoxaphos-                                              phine                                                                         10,10-Dihydro-10-phenyl-                                                                     12.0     1.27     0.61                                         10-[[(2-propenyloxy)-                                                         carbonyl]imino]-                                                              10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-phenyl-                                                                     10.5     1.13     0.61                                         10-[[(2-propynyloxy)-                                                         carbonyl]imino]-                                                              10 .sub.--H--phenoxaphosphine                                                 10-[[(Cyclopentyloxy)-                                                                       14.0     1.71     0.60                                         carbonyl]imino]-10,10-                                                        dihydro-10-phenyl-                                                            10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-phenyl-                                                                     20.5     2.61     0.59                                         10-[[(3-pyridylmethoxy)-                                                      carbonyl]imino]-                                                              10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-phenyl-                                                                     18.0     2.28     0.40                                         10-[[(4-pyridylmethoxy)-                                                      carbonyl]imino]-                                                              10 .sub.--H--phenoxaphosphine                                                 10,10-Dihydro-10-phenyl-                                                                     10.8*    1.26*    0.74*                                        10-[[(2-pyridylmethoxy)-                                                      carbonyl]imino]-                                                              10 .sub.--H--phenoxaphosphine*                                                10,10-Dihydro-10-imino-                                                                      9.8      1.56     0.18                                         10-phenyl-10 .sub.--H--phenoxa-                                               phosphine, sulfate                                                            10,10-Dihydro-10-imino-                                                                      12.5     1.16     0.66                                         10-phenyl-10 .sub.--H--phenoxa-                                               phosphine, bis(trifluoro-                                                     acetate)                                                                      10,10-Dihydro-10-                                                                            8.0      1.12     0.26                                         phenyl-10 .sub.--H--phenoxa-                                                  phosphine, hydro-                                                             bromide                                                                       10,10-Dihydro-10-imino-                                                                      16.5     2.01     0.59                                         10-phenyl-10 .sub.--H--phenoxa-                                               phosphine, hydrochloride                                                      ______________________________________                                         *Dosage = 50 mg/kg                                                       

The compounds of the present invention have been found to be highlyuseful for lowering plasma renin activity and as diuretics in mammalswhen administered in amounts ranging from about 1.0 mg to about 30 mg/kgof body weight per day. A preferred dosage regimen for optimum resultswould be from about 3.0 mg to about 20.0 mg/kg of body weight per day.Such dosage units are employed that a total of from about 200 mg toabout 1400 mg of active compound for a subject of about 70 kg of bodyweight are administered in a 24 hour period. This dosage regimen may beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. The compounds of this invention are preferably administeredorally but may be administered in any convenient manner such as by theintravenous, intramuscular, or subcutaneous routes, in appropriatequantities.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as a fatty oil. Various other materials maybe present as coatings or to otherwise modify the physical form of thedosage unit. For instance, tablets, pills or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing these dosage unit forms must bepharmaceutically pure and nontoxic.

The sulfate salt of10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine, being stable insolution, may be administered parenterally. Solutions of the sulfatesalt can be prepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glyocos and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms such asbacteria and fungi. The carrier can be a solvent or dispersion mediumcontaining for example, water, ethanol, polyol (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like),suitable mixtures thereof, and vegetable oils. The proper fluidity canbe maintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionsand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars or sodium chloride.Prolonged absorption of the injectable compositions can be brought aboutby the use in the compositions of agents delaying absorption, forexample, aluminum monosterate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the otherrequired ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

As used herein, "pharmaceutically acceptable carrier" includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional medium or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form, as used herein, refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specification for the novel dosageunit forms of the invention are dictated by, and directly dependent on,the unique characteristics of the active material and the particulartherapeutic effect to be achieved, and the limitations inherent in theart of compounding such an active material for the treatment of diseaseof living subjects having a diseased condition in which bodily health isimpaired as herein disclosed in detail.

The invention will be described in greater detail in conjuntion with thefollowing non-limiting examples.

EXAMPLE 110,10-Dihydro-10-[(ethoxycarbonyl)imino]-10-phenyl-10H-phenoxaphosphine

The compound 10-phenyl-10H-phenoxaphosphine was prepared by the methodof J. Granoth, et al., J. Chem. Soc., Perkin II, pp. 697-700 (1972).

A solution of 1.50 g of 10-phenyl-10H-phenoxaphosphine in ether wasfiltered through diatomaceous earth. To the filtrate was added dropwisea solution of 0.95 g of ethyl carbonazidate in 5.7 ml of ether. Thismixture was stirred overnight, then the crystals were collected, washedwith ether and dried in vacuo for 3 hours at 50° C., giving 970 mg ofthe desired product, mp 160°-162° C. (dec.).

EXAMPLE 210,10-Dihydro-10-[(methoxycarbonyl)imino]-10-phenyl-10H-phenoxaphosphine

To a solution of 1.46 g of 10-phenyl-10H-phenoxaphosphine in 20 ml ofether was added with stirring, a solution of 0.8 g of methylcarbonazidate in 7 ml of ether. This mixture was stirred for 2 hours,then allowed to stand and the crystals were collected, washed with etherand dried overnight at 40° C., giving 1.26 g of the desired product, mp181°-184° C. (dec.).

EXAMPLE 310,10-Dihydro-10-[[(1-methylethoxy)carbonyl]imino]-10-phenyl-10H-phenoxaphosphine

A 1.5 g portion of isopropyl chloroformate was dissolved in 25 ml ofacetonitrile. This solution was stirred at 0.5° C. as 1.0 g of lithiumazide was added. This mixture was stirred for 16 hours, then 50 ml ofether was added and the mixture filtered into a solution of 2.5 g of10-phenyl-10H-phenoxaphosphine in 50 ml of ether. This mixture wasstirred for 30 minutes, then allowed to stand for 3 hours. The solid wascollected, washed with ether and dried in vacuo at 60° C., giving 0.3 gof the desired product, mp 191°-192° C.

EXAMPLE 410,10-Dihydro-10-[[(2-methylpropoxy)carbonyl]-imino]-10-phenyl-10H-phenoxaphosphine

The procedure of Example 3 was repeated using 1.6 g of isobutylchloroformate in place of the isopropyl chloroformate. The finalreaction mixture was evaporated in vacuo to a viscous oil. This oil wasstirred with 100 ml of ether, then the crystals were collected, washedwith ether and dried in vacuo at 60° C., giving 2.1 g of the desiredproduct, mp 142°-143° C.

EXAMPLE 510,10-Dihydro-10-phenyl-10-[[(phenylmethoxy)carbonyl]imino]-10H-phenoxaphosphine

The procedure of Example 4 was repeated using 2.1 g of benzylchloroformate in place of the isobutyl chloroformate, giving 1.7 g ofthe desired product, mp 148°-150° C.

EXAMPLE 610,10-Dihydro-10-[(1H-imidazol-1-ylcarbonyl)imino]-10-phenyl-10H-phenoxaphosphine

To a mixture of 6.0 g of trifluoroacetic acid in 100 ml of acetonitrileat 0° C. was added 5.0 g of lithium azide. This mixture was stirred at0°-5° C. for 90 minutes, then a solution of 11.0 g of10-phenyl-10H-phenoxaphosphine and 7.0 g of N,N-carbonyldiimidazole in200 ml of acetonitrile was added. This mixture was stirred at roomtemperature for 5 hours, then diluted with 500 ml of water. The solidwas collected, washed with water and dried in vacuo at 60° C., giving13.5 g of10,10-dihydro-10-[(1H-imidazol-1-ylcarbonyl)imino]-10-phenyl-10H-phenoxaphosphine,mp 225°-226° C.

EXAMPLE 710-[[(Cyclopropylmethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphine

A 1.0 portion of cyclopropylmethanol was dissolved in 100 ml of1,2-dimethoxyethane. This solution was treated with 0.6 g of 50% sodiumhydride in oil and stirred for 30 minutes. A 3.8 g portion of10,10-dihydro-10-[(1H-imidazol-1-ylcarbonyl)imino]-10-phenyl-10H-phenoxaphosphinewas added and this mixture was stirred at reflux for 16 hours, thencooled, diluted with 200 ml of water and stored at -10° C. Thissuspension was extracted with 500 ml of dichloromethane. Thedichloromethane layer was dried over magnesium sulfate, filtered and thefiltrate evaporated to a viscous oil. This oil was stirred with 100 mlof ether overnight, then the precipitate was collected, washed withether and dried in vacuo at 60° C., giving 0.3 g of the desired product,mp 163°-166° C.

EXAMPLE 810,10-Dihydro-10-phenyl-10-[[[(tetrahydro-3-furanyl)-oxy]carbonyl]imino]-10H-phenoxaphosphine

A mixture of 0.85 ml of 3-hydroxytetrahydrofuran, 50 ml of1,2-dimethoxyethane and 0.5 g of 50% sodium hydride in oil was stirredfor 1/2 hour. A 3.8 g portion of10,10-dihydro-10-[(1H-imidazol-1-ylcarbonyl)imino]-10-phenyl-10H-phenoxaphosphinewas added, the mixture was refluxed for 6 hours and then concentrated toa thick gum. Water was added and the resulting solid collected andrecrystallized from dichloromethane-hexane with charcoal treatment andrefrigeration, giving 2.50 g of the desired product, mp 164°-166° C.

EXAMPLE 910,10-Dihydro-10-phenyl-10-[[(2-propenyloxy)carbonyl]imino]-10H-phenoxaphosphine

A mixture of 0.5 g of hexane washed 50% sodium hydride, 50 ml of1,2-dimethoxyethane and 0.71 ml of allyl alcohol was stirred at roomtemperature for 45 minutes, then 3.85 g of10,10-dihydro-10-[(1H-imidazol-1-ylcarbonylimino]-10-phenyl-10H-phenoxaphosphine was added. This mixture wasrefluxed for 6 hours, then concentrated to dryness. Water was added tothe residue, the crystals were collected and recrystallized fromdichloromethanediethyl ether with charcoal treatment and refrigeration,giving 3.0 g of the desired product, mp 120°-122° C.

EXAMPLE 1010,10-Dihydro-10-phenyl-10-[[(2-propynyloxy)carbonyl]imino]-10H-phenoxaphosphine

The procedure of Example 8 was repeated, using 0.61 ml of propargylalcohol in place of allyl alcohol. After refluxing, the mixture wasconcentrated to a thick oil. This oil was partitioned between water anddichloromethane. The dichloromethane extract was taken to dryness invacuo and the residue purified by chromatography on silica gel. Elutionwith 75% ethyl acetate:25% hexane, concentration of the eluate todryness in vacuo and recrystallization from dichloromethane-diethylether gave 450 mg of the desired product, mp 170°-173° C.

EXAMPLE 1110-[[(Cyclopentyloxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphine

A mixture of 0.5 g of petroleum ether washed, 50% sodium hydride, 50 mlof 1,2-dimethoxyethane and 0.63 ml of cyclopentanol was stirred for 45minutes, then 3.85 g of10,10-dihydro-10-[(1H-imidazol-1-ylcarbonyl)imino]-10-phenyl-10H-phenoxaphosphinewas added, the mixture was refluxed for 5 hours and then concentrated toa thick oil. Water was added, the mixture was extracted withdichloromethane and concentrated. The residue was purified bychromatography on silica gel, eluting with 75% ethyl acetate:25% hexaneand recrystallized from dichloromethane-diethyl ether, giving 450 mg ofthe desired product, mp 170°-173° C.

EXAMPLE 1210,10-Dihydro-10-phenyl-10-[[(3-pyridylmethoxy)carbonyl]imino]-10H-phenoxaphosphine

A 100 mg portion of 50% sodium hydride in mineral oil was added to astirred solution of 10.9 g of 3-pyridinemethanol. After 20 minutes 17 gof 1,1'-carbonyldiimidazole was added, and stirring continued for fivehours at room temperature. A 4 g portion of anhydrous hydrazine wasadded and the reaction mixture was stirred at room temperature for 16hours. Removal of all volatiles in vacuo left a residue containing3-pyridylmethylcarbazate. This was dissolved in 100 ml of watercontaining 25 ml of concentrated hydrochloric acid. The solution wasstirred at 0°-5° C. as 8.5 g of sodium nitrite in 50 ml of water wasadded dropwise over 30 minutes. The solution was stirred an additional30 minutes at 0°-5° C. and then basified to pH 8 with 10N sodiumhydroxide. Extraction with 300 ml of diethyl ether and removal of thediethyl ether in vacuo left 8.7 g of 3-pyridylmethyl azidoformate. To astirred solution of 5.5 g of 10-phenyl-10H-phenoxaphosphine in 100 ml ofdiethyl ether was added 4.35 g of 3-pyridylmethyl azidoformate in 25 mlof diethyl ether. Heavy gas evolution resulted immediately, and a tackyprecipitate formed that crystallized abruptly on continued stirring.After one hour, the precipitate of the desired product was collected,washed with diethyl ether and dried; yield, 4.8 g; mp 135°-136° C.,resolidifying and then remelting at 165°-166° C.

EXAMPLE 1310,10-dihydro-10-phenyl-10-[[(4-pyridylmethoxy)carbonyl]imino]-10H-phenoxaphosphine

The procedure of Example 9 was repeated, using 1.2 g of4-pyridinemethanol in place of allyl alcohol. After refluxing for 18hours, the mixture was added to 500 ml of ice water. The precipitate wascollected on a filter of diatomaceous earth. Extraction with 250 ml ofboiling dichloromethane, and concentration in vacuo gave a viscous oilwhich was dissolved in 100 ml of boiling diethyl ether. Cooling at -10°C. gave 0.75 g of the desired product as white crystals, mp 137°-139° C.

EXAMPLE 1410,10-Dihydro-10-phenyl-10-[[(2-pyridylmethoxy)carbonyl]imino]-10H-phenoxaphosphine

The procedure of Example 13 was repeated, using 1.2 g of2-pyridinemethanol in place of 4-pyridinemethanol. The crude product waspurified by chromatography on silica gel, eluting with 75% ethylacetate:25% hexane. After removal of the solvents in vacuo, andrecrystallization of the residue from diethyl ether, 183 mg of thedesired product was obtained, mp 128°-129° C.

EXAMPLE 15 Preparation of Compressed Tablet

    ______________________________________                                        Ingredient              mg/Tablet                                             ______________________________________                                        10,10-Dihydro-10-[(ethoxycarbonyl)imino]-                                                             5-100                                                 10-phenyl-10 .sub.--H--phenoxaphosphine                                       Dibasic Calcium Phosphate NF                                                                          qs                                                    Starch U.S.P.           40                                                    Modified Starch         10                                                    Magnesium Stearate U.S.P.                                                                             1-5                                                   ______________________________________                                    

EXAMPLE 16 Preparation of Hard Shell Capsule

    ______________________________________                                        Ingredient              mg/Capsule                                            ______________________________________                                        10,10-Dihydro-10-[(ethoxycarbonyl)imino]-                                                             5-100                                                 10-phenyl-10 .sub.--H--phenoxaphosphine                                       Lactose, Spray Dried    qs                                                    Magnesium Stearate U.S.P.                                                                             1-10                                                  ______________________________________                                    

EXAMPLE 17 Preparation of Oral Suspension

    ______________________________________                                        Ingredient              Amount                                                ______________________________________                                        10,10-Dihydro-10-[(ethoxycarbonyl)imino]-                                                             1-5%                                                  10-phenyl-10 .sub.--H--phenoxaphosphine                                       Veegum                  0.1-2.0%                                              Methyl paraben          0.08%                                                 Propyl paraben          0.02%                                                 Sucrose/Sorbitol        20-80%                                                Flavor                  qs                                                    Water                   qs to 100%                                            ______________________________________                                    

EXAMPLE 18 10,10-Dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,sulfate

To a stirred suspension of 2.7 g of 10-phenyl-10H-phenoxaphosphine in 20ml of anhydrous methanol, was added dropwise over 5 minutes, a solutionof 1.1 g of hydroxylamine O-sulfonic acid in 7 ml of anhydrous methanol.The reaction mixture was stirred for 3 hours, during which time itbecame homogeneous, and was then filtered into 200 ml of ether andstirred for 30 minutes. The colorless solid was collected and washedwith ether, giving 2.5 g of the desired product, mp 210°-218° C.

EXAMPLE 1910-[[(1,1-Dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphine

To a solution of 13.8 g of 10-phenyl-10H-phenoxaphosphine in 250 ml ofether was added a solution of 11.5 g of t-butyl carbonazidate in 50 mlof ether. The mixture was stirred for 2 hours, producing vigorous gasevolution and a heavy white precipitate, which was collected, washedwith ether and dried in vacuo at 60° C., giving 18.0 g of the desiredcompound, mp 229°-231° C. (dec.).

EXAMPLE 20 10,10-Dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,sulfate

A 1 g portion of10-[[(1,1-dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphinewas added to 5 ml of 50% aqueous sulfuric acid. This mixture was stirredfor 18 hours, then the solid was collected, washed with water, slurriedin 5 ml of acetone for 30 minutes and the solid collected and dried,giving 0.2 g of the desired product, mp 215°-225° C.

EXAMPLE 21 10,10-Dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,bis(trifluoroacetate)

A 1 g portion of10-[[1,1-dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphinewas added to 5 ml of trifluoroacetic acid. The solution was allowed tostand for 2 hours, then was added to 400 ml of ether and taken todryness in vacuo. The residue was triturated with ether and the solidcollected, washed with ether and dried in vacuo, giving 0.5 g of thedesired product, mp 115°-118° C.

EXAMPLE 22 10,10-Dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,hydrobromide

A suspension of 1.8 g of10-[[(1,1-dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphinein 15 ml of aqueous 48% hydrobromic acid was stirred for 3 days. Theinsolubles were collected, washed with a little water and thentriturated with 15 ml of acetone. The insoluble product was collected,washed with acetone and then dried in vacuo at 60° C., giving 0.85 g ofthe desired product, mp 283°-286° C.

EXAMPLE 23 10,10-Dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,hydrochloride

A solution of 1.5 g of10[[(1,1-dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphinein 20 ml of dichloromethane was added to 100 ml of ethanol saturatedwith dry hydrogen chloride. The mixture was stirred for one day, thenthe solid was collected, washed with ether and dried in vacuo at 60° C.,giving 0.8 g of the desired product, mp 312°-315° C.

EXAMPLE 24 10,10-Dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,hydrochloride

A 1.8 g portion of10-[[(1,1-dimethylethoxy)carbonyl]imino]-10,10-dihydro-10-phenyl-10H-phenoxaphosphinewas added to 15 ml of 37% aqueous hydrochloric acid. This mixture wasstirred for one hour, then the solid was collected, washed with waterand acetone, and dried in vacuo, giving 0.7 g of the desired product, mp310°-312° C.

EXAMPLE 2510,10-Dihydro-10-[(ethoxycarbonyl)imino]-10-phenyl-10H-phenoxaphosphine

A mixture consisting of 3.9 g of10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine, sulfate, 5 ml oftriethylamine and 50 ml of acetonitrile is stirred as 1.2 go of ethylchloroformate is added dropwise. The mixture is stirred for 4-8 hoursand then clarified. Removal of the solvent and excess triethylamine fromthe filtrate gives the desired compound.

EXAMPLE 2610,10-Dihydro-10-[(methoxycarbonyl)imino]-10-phenyl-10H-phenoxaphosphine

The procedure of Example 25 is repeated, using 1.1 g of methylchloroformate in place of the ethyl chloroformate, giving the desiredcompound.

We claim:
 1. A compound of the formula: ##STR10## wherein n is aninteger 1 or 2 and X is sulfate, trifluoroacetate, bromide or chloride.2. The compound according to claim 1,10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine, sulfate.
 3. Thecompound according to claim 1,10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine,bis(trifluoroacetate).
 4. The compound according to claim 1,10,10-dihydro-10-imino-10-phenyl-10H-phenoxaphosphine, hydrobromide.